This invention relates to a method for preventing or inhibiting the transmission of HIV to uninfected cells.
Various compounds have been described as inhibitors of human immunodeficiency virus type 1 (HIV-1) in vitro hand are targeted at the virus-encoded reverse transcriptase (RT), e.g., nevirapine, pyridinone, TIBO, BHAP, TSAO, and quinoxaline. U.S. Pat. No. 5,268,389 describes certain thiocarboxylate ester compounds useful for inhibiting the replication of HIV. Copending U.S. patent application Ser. No. 08/565,493, filed on Nov. 30, 1995, describes certain methylfuranyl- and methylthienyl-pentenylether derivatives which are inhibitory of the replication of wild-type HIV-1 and HIV-1 reverse transcriptase mutant strains.
The currently approved drugs for the clinical treatment of HIV infection include the dideoxynucleosides AZT and 3TC, which inhibit the viral reverse transcriptase, and saquinavir, which inhibits the viral protease. These drugs are designed to be effective in patients already infected with HIV, in order to improve both the quality and extent of life of patients afflicted with this incurable disease.
However, there is a crucial need to identify therapeutic strategies that will minimize the spread of HIV from already-infected individuals to non-infected individuals. This includes the development of anti-HIV vaccines. Unfortunately, despite considerable effort and expense, this strategy has been so far unsuccessful.
Heterosexual contact is the primary mode of transmission of HIV infection worldwide. See Merson, M. H., Science 260: 1266-1268 (1993). Thus, a retrovirucidal spermicide or vaginal microbiocide could be an effective strategy to minimize the spread of HIV. So far, compounds considered as potential retrovirucides/vaginal microbiocides include virus envelop-disrupting agents, such as nonoxynol-9 [Roddy et al, Int. J. STD AIDS 4: 165-170 (1993), and inhibitors of HIV-CD4 receptor interaction, such as dextran sulfate [Mitsuya et al, Science 240: 646-649 (1988)] and modified xcex2-lactoglobulin [Neurath et al, Nature Med. 2: 230-234 (1996)].
Pauwels and De Clercq, J. Acquired Immun. Def. Syndromes Hum Retrovirol. 11: 211-221 (1996) describe nonnucleoside inhibitors of HIV RT (xe2x80x9cNNIRTxe2x80x9d) as potentially useful as retrovirucides/vaginal microbicides. The NNIRT typically are highly hydrophobic molecules, and thus readily traverse membrane barriers such as that surrounding the HIV core by passive diffusion. However, this property of NNIRT might also facilitate inhibitor efflux from the virion, in the absence of sufficient extra-virion levels of the NNIRT. In order for the NNIRT to be a truly effective retrovirucide, the NNIRT should possess some property that will prolong its residence within the virion.
Ideally, retrovirucidal agents should fulfill several requirements. They should be effective directly on the virus. Retrovirucides should be effective at replication steps prior to integration of proviral DNA into the infected host cell genome. Although protease inhibitors prevent maturation of newly-produced virion particles, they are ineffective against pre-existing mature infectious HIV. Retrovirucides should be absorbable by uninfected cells, in order to provide a barrier to infection by residual active virus. Retrovirucides should be effective at non-cytotoxic concentrations readily attainable in vivo.
It is a purpose of this invention to provide a method to prevent or inhibit the transmission of HIV to uninfected cells whereby HIV infectivity is effectively inhibited or eliminated, by exposure of the virus or cells infected with the virus, to certain methylfuranyl- and methylthienyl-pentenylether derivatives, prior to contact with the uninfected cells. It is also the purpose of this invention to provide a method for treating uninfected cells with certain methylfuranyl- and methylthienyl-pentenylether derivatives to render the uninfected cells refractory to subsequent HIV infection.
This invention relates to a method for the prevention or inhibition of the transmission of HIV to susceptible uninfected cells by administering to the HIV or to cells infected with the HIV, an effective amount of a compound of the formula 
wherein X is O or S,
prior to the HIV or the cells infected with HIV, contacting the uninfected cells.
This invention relates to a method for preventing or inhibiting the transmission of HIV to susceptible uninfected cells by administering to the uninfected cells a prophylactically effective amount of a compound of the formula 
wherein X is O or S,
prior to the HIV or cells infected with HIV, contacting the uninfected cells.
This invention additionally relates to a contraceptive vehicle comprising a means for birth control and an HIV-protective amount of a compound of formula I.